Fungus infections have become the major cause for the high morbidity and mortality in immunodeficiency patients. During the past 20 years, the incidence of mycotic infection has increased significantly. The high-risk population for the fungus infection includes critical patients, surgical patients and the patients with HIV-infection, leukemia as well as other tumors. Additionally, the organ transplant recipients are also the high-risk population for fungus infection.
Echinocandins, as a kind of novel anti-fungal medicaments, are effective in treating Candida- or aspergillus-infections, and the examples of which are Caspofungin and Micafungin. The echinocandins inhibit the fungi by inhibiting the formation of 1,3-β glucosidic bond, thereby reducing the toxicity toward the human and the side effects, while maintaining high efficiency. Therefore, compared with the traditional anti-fungal medicaments, the echinocandins are safer when they are used.
FK463 (Micafungin) is the compound of Formula III, which is obtained by removing the side-chain of compound FR901379 of Formula I through enzymolysis for forming compound FR179642 of Formula II, and then chemically modifying compound FR179642. Therefore, the production of compound of Formula I obtained through fermentation is very important for obtaining Micafungin.
However, the production for the compound of Formula I through fermentation maintains at low level for a long time. Great efforts have been made for seeking a medium with low-cost and high-production, but little progress has been made, therefore it is more difficult to prepare the compound of Formula I, thus increasing the cost and price for FK463. Therefore, it is urgent to find a method for synthesizing the compound of Formula I with low cost and high efficiency.
Fujisawa Pharmaceutical Co Ltd (Japan) has obtained A-3 medium by replacing corn starch with soluble starch to reduce the viscosity of medium upon sterilization and adding sulfate and phosphate to control pH during the fermentation (Improvement of FR901379 production by mutant selection and medium optimization, Journal of Bioscience and Bioengineering, VOL 107 No. 5, 530-534, 2009). Afterwards, Fujisawa further improved A-3 medium by adding high concentration of ammonium sulfate to reduce the viscosity and replacing cottonseed meal with corn steep liquid, thereby obtaining medium A-4 for higher production of the compound of Formula I (Scale-up fermentation of echinocandin type antibiotic FR901379, Journal of Bioscience and Bioengineering, VOL 109 No. 2, 138-144, 2010).
However, it is necessary to further increase the production of compound of Formula I. And the viscosity of the above medium is still very high, and the mycelia form pellet during the fermentation, all of which are adverse to the dissolved oxygen control and subsequent filtering operation.
The inventors found a medium for increasing the production of compound of Formula I through creative works and great amount of experiments. Using the medium in the fermentation, the viscosity of the culture is low, the dissolved oxygen can be readily controlled and the mycelia won't form pellet.
